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1.
Genes Chromosomes Cancer ; 54(11): 702-15, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26274016

RESUMO

Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub-Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub-Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment-resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT-associated genes and evaluated whole-genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow-up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment-resistant.


Assuntos
Aberrações Cromossômicas , Genes do Tumor de Wilms , Neoplasias Renais/genética , Tumor de Wilms/genética , Pré-Escolar , Estudos de Coortes , Feminino , Dosagem de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Quênia , Masculino , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
Nat Methods ; 11(8): 809-15, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24973947

RESUMO

MicroRNAs are important negative regulators of protein-coding gene expression and have been studied intensively over the past years. Several measurement platforms have been developed to determine relative miRNA abundance in biological samples using different technologies such as small RNA sequencing, reverse transcription-quantitative PCR (RT-qPCR) and (microarray) hybridization. In this study, we systematically compared 12 commercially available platforms for analysis of microRNA expression. We measured an identical set of 20 standardized positive and negative control samples, including human universal reference RNA, human brain RNA and titrations thereof, human serum samples and synthetic spikes from microRNA family members with varying homology. We developed robust quality metrics to objectively assess platform performance in terms of reproducibility, sensitivity, accuracy, specificity and concordance of differential expression. The results indicate that each method has its strengths and weaknesses, which help to guide informed selection of a quantitative microRNA gene expression platform for particular study goals.


Assuntos
MicroRNAs/genética , Controle de Qualidade , Reprodutibilidade dos Testes
3.
Br J Nutr ; 110(11): 2011-9, 2013 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23597267

RESUMO

Obesity increases the risk of developing bacterial and viral infections compared with normal weight. In a 7-week double-blind, randomised, cross-over trial, twenty obese volunteers (BMI between 30 and 40 kg/m²) were fed freeze-dried strawberry powder or strawberry-flavoured placebo preparations to determine the effects of dietary strawberries on immune function. Blood was collected at six time points during the study and peripheral blood mononuclear cells (PBMC) were isolated at each time point and activated with CD3 plus CD28 antibodies (T-lymphocyte activation) or lipopolysaccharide (LPS, monocyte activation). Interferon-γ, TNF-α, IL-4 and IL-10 were measured in supernatants from the activated T cells. Supernatants from the activated monocytes were analysed for the production of TNF-α, IL-1ß, IL-6 and IL-8. PBMC were pre-stained with PKH (Paul Karl Horan) dye and activated with CD3 plus CD28 antibodies to determine the proliferative responses of CD4⁺ and CD8⁺ T-lymphocytes by flow cytometry. To detect global changes in gene expression, microarray analysis was performed on LPS- and vehicle-treated PBMC from two subjects before and after the strawberry intervention. No difference was observed for the production of T-cell cytokines between the intervention groups. The production of TNF-α was increased in the supernatants from LPS-activated PBMC in the group consuming strawberries compared with the placebo. A modest increase in the proliferation of the CD8⁺ T-lymphocyte population was observed at 24 h post-activation. These data suggest that dietary strawberries may increase the immunological response of T-lymphocytes and monocytes in obese people who are at greater risk for developing infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Suplementos Nutricionais , Fragaria , Fatores Imunológicos/uso terapêutico , Monócitos/imunologia , Obesidade/dietoterapia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Índice de Massa Corporal , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Células Cultivadas , Estudos Cross-Over , Citocinas/genética , Citocinas/metabolismo , Método Duplo-Cego , Feminino , Frutas , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Fator de Necrose Tumoral alfa/genética , Regulação para Cima , Adulto Jovem
4.
Environ Pollut ; 167: 163-70, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22575097

RESUMO

Larval zebrafish (Danio rerio) were exposed (96 h) to selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and changes in transcriptomes analyzed by Affymetrix GeneChip Zebrafish Array were evaluated to enhance understanding of biochemical pathways and differences between these SSRIs. The number of genes differentially expressed after fluoxetine exposure was 288 at 25 µg/L and 131 at 250 µg/L; and after sertraline exposure was 33 at 25 µg/L and 52 at 250 µg/L. Same five genes were differentially regulated in both SSRIs indicating shared molecular pathways. Among these, the gene coding for FK506 binding protein 5, annotated to stress response regulation, was highly down-regulated in all treatments (results confirmed by qRT-PCR). Gene ontology analysis indicated at the gene expression level that regulation of stress response and cholinesterase activities were influenced by these SSRIs, and suggested that changes in transcription of these genes could be used as biomarkers of SSRI exposure.


Assuntos
Fluoxetina/toxicidade , Expressão Gênica/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Larva , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
J Nutr ; 142(3): 630S-634S, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22279143

RESUMO

Stearidonic acid (SDA), a highly unsaturated (n-3) PUFA, is effectively metabolized to EPA with a bioequivalence of ~5:1 as determined by the omega-3 index, a biomarker for risk of cardiovascular disease. The AHA has recommended that individuals increase their consumption of highly unsaturated (n-3) PUFA, particularly EPA and DHA, but there are concerns about achieving the recommendations through fish consumption. SDA is considered a biological surrogate for EPA. SDA-enriched soybean oil whose SDA content is ~30% could be a novel mechanism to seamlessly incorporate highly unsaturated (n-3) PUFA into the food supply; however, the effects of SDA are poorly understood, particularly at the transcriptional level. This paper reviews the human literature of the effects of dietary SDA on circulating lipids as directly compared with EPA at bioequivalent doses. These results were then compared to the effects of SDA on expression patterns of hepatic lipolytic and lipogenic genes in swine fed diets containing SDA at levels similar with those doses used in human trials. Supplementing SDA at doses of 3.7-4.2 g/d, of which the bioequivalence to EPA is ≤1 g/d, had little impact on modifying circulating TG and total, LDL, and HDL cholesterol, recapitulating the results with EPA at doses of 1.0-1.5 g/d. These results were generally supported by the gene expression patterns in swine. Although many lipolytic and lipogenic genes remained unchanged, several lipogenic genes were downregulated and a number of other biomarkers considered atheroprotective, such as C-reactive protein and paraoxonase, were favorably modified.


Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Biomarcadores/sangue , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipólise/efeitos dos fármacos , Lipólise/genética , Equivalência Terapêutica
6.
Infect Immun ; 80(3): 968-74, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22144491

RESUMO

Toxoplasma gondii is the causative agent of toxoplasmosis in human and animals. In a mouse model, T. gondii strains can be divided into three groups, including the virulent, intermediately virulent, and nonvirulent. The clonal type I, II, and III T. gondii strains belong to these three groups, respectively. To better understand the basis of virulence phenotypes, we investigated mouse gene expression responses to the infection of different T. gondii strains at day 5 after intraperitoneal inoculation with 500 tachyzoites. The transcriptomes of mouse peritoneal cells showed that 1,927, 1,573, and 1,009 transcripts were altered more than 2-fold by type I, II, and III infections, respectively, and that the majority of altered transcripts were shared. Overall transcription patterns were similar in type I and type II infections, and both had greater changes than infection with type III. Quantification of parasite burden in mouse spleens showed that the burden with type I infection was 1,000 times higher than that of type II and that the type II burden was 20 times higher than that of type III. Fluorescence-activated cell sorting revealed that type I and II infections had comparable macrophage populations, and both were higher than the population with type III infection. In addition, type I infection had a higher percentage of neutrophils than type II and III infections. Taken together, these results suggested that there is a common gene expression response to T. gondii infection in mice. This response is further modified by parasite strain-specific factors that determine their distinct virulence phenotypes.


Assuntos
Perfilação da Expressão Gênica , Expressão Gênica , Interações Hospedeiro-Patógeno , Toxoplasma/imunologia , Toxoplasma/patogenicidade , Animais , Modelos Animais de Doenças , Feminino , Injeções Intraperitoneais , Macrófagos/imunologia , Camundongos , Neutrófilos/imunologia , Baço/parasitologia , Toxoplasmose Animal
7.
Environ Sci Technol ; 45(5): 1962-9, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21280650

RESUMO

Microcystis blooms occur worldwide and threaten aquatic ecosystems and human health. Sublethal effects on early developmental stages of fish are largely unknown, and research has mainly focused on microcystin toxins (such as MC-LR) rather than Microcystis cells. We exposed (96 h) zebrafish larvae to purified MC-LR (0-1000 µg/L) or lyophilized Microcystis aeruginosa containing 4.5 µg/L MC-LR and evaluated changes in global gene expression (Affymetrix GeneChip zebrafish genome arrays). Significant changes in gene expression (≥ 1.7-fold change, p < 0.0001) were determined with Rosetta Resolver 7.0, and ontology analysis was conducted with the DAVID bioinformatics tool. The number of differentially expressed genes relative to control increased with MC-LR concentration and included genes related to known mechanisms of action for MC-LR in mammals and older life stages of fish, as well as genes unique to larval zebrafish. Up-regulation of vitellogenin genes (vtg) (19.2-fold to >100-fold on arrays; 619.3-fold confirmed by quantitative PCR) was observed in Microcystis-exposed larvae but not in larvae exposed to MC-LR. Up-regulation of vtg indicates exposure to estrogenic substance(s) and suggests that Microcystis may be a natural source of environmental estrogens. Concerns about effects of Microcystis blooms may extend beyond those associated with the microcystin toxin.


Assuntos
Disruptores Endócrinos/toxicidade , Expressão Gênica/efeitos dos fármacos , Microcistinas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Disruptores Endócrinos/metabolismo , Larva/efeitos dos fármacos , Toxinas Marinhas , Microcistinas/metabolismo , Microcystis/crescimento & desenvolvimento , Microcystis/metabolismo , Poluentes Químicos da Água/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
8.
J Nutrigenet Nutrigenomics ; 2(2): 64-77, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19690433

RESUMO

BACKGROUND/AIM: High-calcium diets modulate energy metabolism and suppress inflammatory stress. These effects are primarily mediated by calcium suppression of calcitriol. We have now investigated the effect of additional components in dairy products [branched-chain amino acids (BCAA) and angiotensin-converting enzyme inhibitors (ACEi)] on adipocyte and muscle metabolism in an animal model of diet-induced obesity. METHODS: aP2-agouti mice were fed four different 70% restricted diets for 6 weeks: basal-restricted diet (0.4% Ca), nonfat dry milk (1.2% Ca), calcium-depleted milk (0.4% Ca), or basal-restricted diet (0.4% Ca) with supplemented BCAA/ACEi. A high-density oligonucleotide microarray approach was used to compare the effects on energy metabolism. RESULTS: Lipogenic genes in adipose tissue were downregulated in the milk group while in muscle protein synthetic pathways were stimulated by the Ca-depleted and low Ca/BCAA/ACEi diets. Pathways involved in inflammation were altered in adipose tissue and muscle by all three diet treatment groups. CONCLUSIONS: The results support our previous findings that calcium and BCAA contribute to the alteration of energy partitioning between adipose tissue and muscle. They provide further evidence for a calcium-independent effect of BCAA and ACEi in energy metabolism and inflammation.


Assuntos
Laticínios/análise , Dieta/efeitos adversos , Metabolismo Energético , Obesidade/etiologia , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Proteína Agouti Sinalizadora/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Cálcio da Dieta/administração & dosagem , Inflamação/etiologia , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Leite/química , Músculos/metabolismo , Nutrigenômica , Obesidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo , Fatores de Risco
9.
Funct Integr Genomics ; 9(4): 537-47, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19543758

RESUMO

High explosives such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and 2,4,6-trinitrotoluene (TNT) are important contaminants in the environment and phytoremediation has been viewed as a cost-effective abatement. There remains, however, an insufficient knowledge-base about how plants respond to explosives, especially in the steady state. Microarray analysis was conducted on Arabidopsis thaliana that were grown in Murashige and Skoog media containing steady-state levels of 0.5 mM RDX or 2.0 microM TNT to study the effect of these compounds on its transcriptional profile. Our results for both RDX and TNT were consistent with the existing theory for xenobiotic metabolism in plants. Among the genes that were differentially expressed included oxidoreductases, cytochrome P450s, transferases, transporters, and several unknown expressed proteins. We discuss the potential role of upregulated genes in plant metabolism, phytoremediation, and phytosensing. Phytosensing, the detection of field contamination using plants, is an end goal of this project.


Assuntos
Arabidopsis , Biodegradação Ambiental , Substâncias Explosivas/metabolismo , Triazinas/metabolismo , Trinitrotolueno/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Humanos , Metanálise como Assunto , Análise em Microsséries , Dados de Sequência Molecular
10.
Vet Clin Pathol ; 38(1): 13-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19228364

RESUMO

BACKGROUND AND OBJECTIVE: We investigated hepatic gene expression in dogs with experimentally induced nutritional iron deficiency (ID). Our hypothesis was that ID would result in decreased hepcidin gene expression, and possibly in altered expression of other genes associated with iron metabolism. METHODS: Liver biopsies were collected from each of 3 dogs before induction of ID, at the point of maximal ID, and after resolution of ID. Using Affymetrix microarray technology and analytical tools specifically designed for microarray data, we identified genes that had at least a 2-fold change in expression in response to ID. Four genes were selected for further analysis by reverse transcriptase PCR (RT-PCR). RESULTS: Dogs with ID had markedly decreased expression of the hepcidin gene (mean decrease of 40-fold for one probe and >100-fold for another probe) and increased expression of the transferrin receptor gene (mean increase of >7-fold). There was also mildly decreased expression of the "similar to calreticulin" gene and a gene of unknown function. Results of RT-PCR analysis were consistent with microarray findings. CONCLUSION: Changes in hepcidin and transferrin receptor gene expression were consistent with the known biology of iron metabolism. The decrease in expression of a gene identified as "similar to calreticulin," while not statistically significant, was consistent with the findings of other investigators that suggest iron plays a role in calreticulin expression.


Assuntos
Anemia Ferropriva/veterinária , Doenças do Cão/metabolismo , Regulação da Expressão Gênica/fisiologia , Fígado/metabolismo , Anemia Ferropriva/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Cães , Feminino , Ferro da Dieta , Masculino
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